A. Field of the Invention
This invention pertains generally to treating infections caused by gram-negative bacteria. More specifically, the invention described herein pertains to treating gram-negative infections by inhibiting activity of UDP-3-O—(R-3-hydroxydecanoyl)-N-acetylglucosamine deacetylase (LpxC). The present invention provides small molecule inhibitors of LpxC, pharmaceutical formulations containing such inhibitors, methods of treating subjects with such pharmaceutical formulations, and methods of preparing such pharmaceutical formulations and inhibitors. The invention described herein pertains to treating gram-negative infections by administering compounds capable of inhibiting activity of UDP-3-O—(R-3-hydroxydecanoyl)-N-acetylglucosamine deacetylase (LpxC), either alone or in combination with administering a second antibacterial compound.
B. Introduction
Over the past several decades, the frequency of antimicrobial resistance and its association with serious infectious diseases have increased at alarming rates. The problem of antibacterial resistance is compounded by the existence of bacterial strains resistant to multiple antibacterials. Thus there is a need for new antibacterials, particularly antibacterials with novel mechanisms of action. A previously unexploited but highly conserved target, LpxC, provides a new opportunity for developing broad-spectrum antibacterial small molecules that comprise a new class of active bactericidal chemical entities that should encounter little, if any, naturally-occurring, target-related resistance. LpxC (the enzyme uridyldiphospho-3-O—(R-hydroxydecanoyl)-N-acetylglucosamine deacetylase) is present across all Gram-negative bacterial species of interest and is involved in the first committed step in outer membrane biosynthesis. Thus LpxC is essential for survival and presents an ideal target for antibiotic activity in Gram-negative bacterial species.
Researchers have identified some compounds with antibacterial activity that target lipid A biosynthesis. For example, Jackman et al. (J. Biol. Chem., 2000, 275(15), 11002-11009); Wyckoff et al. (Trends in Microbiology, 1998, 6(4), 154-159); U.S. Patent Application Publication No. 2001/0053555 (published 20 Dec. 2001, corresponding to International PCT Publication No. WO 98/18754, published 7 May 1998); International PCT Publication No. WO 00/61134 (published 19 Oct. 2000); U.S. Patent Application Publication No. 2004/0229955 (published 18 Nov. 2004); International PCT Publication No. WO 2008/027466 (published 6 Mar. 2008); International PCT Publication No. WO 2008/105515 (published 4 Sep. 2008); International PCT Publication No. WO 2008/154642 (published 18 Dec. 2008); International PCT Publication No. WO 2009/158369 (published 30 Dec. 2009); International PCT Publication No. WO 2010/017060 (published 11 Feb. 2010); International PCT Publication No. WO 2010/024356 (published 4 Mar. 2010); International PCT Publication No. WO 2010/031750 (published 25 Mar. 2010); International PCT Publication No. WO 2010/032147 (published 25 Mar. 2010); International PCT Publication No. WO 2010/100475 (published 10 Sep. 2010); International PCT Publication No. WO 2011/045703 (published 21 Apr. 2011); International PCT Publication No. WO 2011/073845 (published 23 Jun. 2011); and International PCT Publication No. WO 2011/132712 (published 27 Oct. 2011) all disclose compounds having antibacterial anti-LpxC activity. The commercial development of these LpxC inhibitors has been complicated by toxicity of these compounds in mammalian animals at concentrations at or near those required for antibacterial activity.
Although there have been advances in the field, there remains a need for LpxC inhibitors that have activity as bactericidal agents against gram-negative bacteria and have an acceptable efficacy and toxicity/tolerance profile. It is, accordingly, an object of this invention to provide compounds and combinations of such compounds for use in the preparation of non-toxic antibacterials and other pharmaceuticals capable of inhibiting gram-negative bacterial infections.